Vascular dysfunction in a murine model of severe hemolysis. Blood 2008 Jul 15;112(2):398-405
Date
05/15/2008Pubmed ID
18477769Pubmed Central ID
PMC2442749DOI
10.1182/blood-2007-12-126714Scopus ID
2-s2.0-47649122900 (requires institutional sign-in at Scopus site) 43 CitationsAbstract
Spectrin is the backbone of the erythroid cytoskeleton; sph/sph mice have severe hereditary spherocytosis (HS) because of a mutation in the murine erythroid alpha-spectrin gene. sph/sph mice have a high incidence of thrombosis and infarction in multiple tissues, suggesting significant vascular dysfunction. In the current study, we provide evidence for both pulmonary and systemic vascular dysfunction in sph/sph mice. We found increased levels of soluble cell adhesion molecules in sph/sph mice, suggesting activation of the vascular endothelium. We hypothesized that plasma hemoglobin released by intravascular hemolysis initiates endothelial injury through nitric oxide (NO) scavenging and oxidative damage. Likewise, electron paramagnetic resonance spectroscopy showed that plasma hemoglobin is much greater in sph/sph mice. Moreover, plasma from sph/sph mice had significantly higher oxidative potential. Finally, xanthine oxidase, a potent superoxide generator, is decreased in subpopulations of liver hepatocytes and increased on liver endothelium in sph/sph mice. These results indicate that vasoregulation is abnormal, and NO-based vasoregulatory mechanisms particularly impaired, in sph/sph mice. Together, these data indicate that sph/sph mice with severe HS have increased plasma hemoglobin and NO scavenging capacity, likely contributing to aberrant vasoregulation and initiating oxidative damage.
Author List
Frei AC, Guo Y, Jones DW, Pritchard KA Jr, Fagan KA, Hogg N, Wandersee NJAuthors
Neil Hogg PhD Associate Dean, Professor in the Biophysics department at Medical College of WisconsinKirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsDisease Models, Animal
Hemoglobins
Hemolysis
Hypertension, Pulmonary
Liver
Mice
Mice, Mutant Strains
Nitric Oxide
Spectrin
Spherocytosis, Hereditary
Vasodilation
Xanthine Oxidase
